We propose to develop a novel anti-HIV therapeutic that blocks integration of retroviral DNA into the host genome by specifically targeting HIV-1 integrase (IN) for ubiquitination and subsequent catalytic elimination by proteolytic degradation. L-chicoric acid, a selective active site binding inhibitor of IN will be functionalized for selective conjugation with multiple linkers containing a ubiquitination recognition signal. The compounds developed will be evaluated for their ability to target IN for rapid proteolytic degradation via the ubiquitin/26S proteosome pathway in reticulocyte lysates. Active drugs will be submitted to the NCI AIDS Antiviral Drug Screen to demonstrate low dose efficacy and high therapeutic index in the inhibition of HIV replication in tissue culture. The technology is applicable to binding molecules targeting multiple sites on a single protein which is a novel strategy to counter rapid HIV mutation. Optimized ubiquitination recognition components from this proposal can also be used with specific binding molecules to target other intracellular protein functions for rapid proteolytic degradation. PROPOSED COMMERCIAL APPLICATION Development of anti-HIV drugs which blocks HIV replication by specifically targeting HIV-1 integrase for catalytic degradation. No integrase inhibitors have yet been commercialized. A drug that prevents integrase activity will significantly advance the capability to treat HIV infected individuals which are projected to number 30-40 million world-wide by the year 2000.